The mammalian immune system provides a means for the recognition and elimination of tumor cells, other pathogenic cells, and invading foreign pathogens. While the immune system normally provides a strong line of defense, there are still many instances where cancer cells, other pathogenic cells, or infectious agents evade a host immune response and proliferate or persist with concomitant host pathogenicity. The capacity of cancer cells to develop resistance to therapeutic agents, and the adverse side effects of many of the currently available chemotherapeutic agents, particularly in high doses, highlight the need for the development of new therapies with reduced capacity for the development of host resistance and with reduced host toxicity.
Researchers have developed therapeutic protocols for destroying cancer cells by targeting cytotoxic compounds specifically to cancer cells. These protocols utilize toxins conjugated to ligands that bind to receptors unique to or overexpressed by cancer cells in an attempt to minimize delivery of the toxin to normal cells. Another approach for selectively targeting populations of cancer cells or other pathogenic cells in a host is to enhance the host's immune response against the pathogenic cells. One reported strategy for immunotherapy is to bind antibodies, for example, genetically engineered multimeric antibodies, to the tumor cell surface to display the constant region of the antibodies on the cell surface and thereby induce tumor cell killing by various immune system-mediated processes (De Vita, V. T., Biologic Therapy of Cancer, 2d ed. Philadelphia, Lippincott, 1995; Soulillou, J. P., U.S. Pat. No. 5,672,486).
Another strategy for relying on host immune competency is the targeting of an anti-T cell receptor antibody or anti-Fc receptor antibody to tumor cell surfaces to promote direct binding of immune cells to tumors (Kranz, D. M., U.S. Pat. No. 5,547,668). A vaccine-based approach has also been described which relies on a vaccine comprising antigens fused to cytokines, with the cytokine modifying the immunogenicity of the vaccine antigen, and, thus, stimulating the immune response to the pathogenic agent (Pillai, S., PCT Publication Number WO 91/11146, published Feb. 7, 1991). Yet another approach for killing unwanted cell populations utilizes IL-2 or Fab fragments of anti-thymocyte globulin linked to antigens to eliminate unwanted T cells (WO 97/37690, published Oct. 16, 1997). There remains a significant need for therapies directed to treatment of disease states characterized by the existence of pathogenic cell populations in an affected host.
The present invention is directed to a method of eliminating cancer cell populations in a host by increasing host immune system recognition of and response to such cell populations. The antigenicity of the cancer cells is increased to enhance the endogenous immune response-mediated elimination of the cancer cells. The method also utilizes the administration of low doses of radiation (e.g., about 0.5 to about 10 Gy per dose) to eliminate the cancer cell populations. The method comprises administration of a ligand-immunogen conjugate wherein the ligand is capable of binding to a population of cancer cells in vivo that uniquely expresses, preferentially expresses, or overexpresses a ligand-binding receptor. The ligand-conjugated immunogen is capable of eliciting antibody production or is capable of being recognized by endogenous or co-administered exogenous antibodies in the host. The immune system-mediated elimination of the cancer cells is directed by the binding of the ligand-conjugated immunogen to a receptor, a transporter, or other surface-presented protein uniquely expressed, overexpressed, or preferentially expressed by the cancer cells. Low doses of radiation (e.g., about 0.5 to about 10 Gy per dose) are administered in combination with the ligand-immunogen conjugates to eliminate the cancer cell populations.
In one illustrative embodiment, a method is provided of enhancing an endogenous immune response-mediated elimination of a population of cancer cells in a host. In one embodiment, the method comprises the steps of administering to the host a composition comprising an immunogen conjugated to a vitamin receptor-binding ligand selected from the group consisting of a vitamin, or an analog or a derivative thereof, and administering to the host a therapeutically effective amount of radiation wherein the amount of radiation ranges from about 0.5 to about 10 Gy per dose.
In another illustrative embodiment, the vitamin is selected from the group consisting of folic acid and other folate receptor-binding ligands. In another embodiment, the immunogen is fluorescein, dinitrophenyl, or an α-galactosyl group. In yet another embodiment, the antibody is exogenous to the host and is co-administered with the conjugate composition. In another embodiment, the method further comprises the step of administering to the host a therapeutic factor such as IL-2, IL-12, IL-15, or combinations thereof, IL-2, IL-12, IL-15, or combinations thereof, in combination with IFN-α or IFN-γ, IL-2, IL-12, IL-15, or combinations thereof, in combination with IFN-α or IFN-γ, or a combination thereof, and GM-CSF. In yet another embodiment, the host has been previously exposed naturally to the immunogen so that the host has a preexisting immunity to the immunogen or the host has been previously exposed to the immunogen by a non-natural process resulting in priming of the host's immune response to the immunogen. In other illustrative embodiments, the endogenous immune response comprises an humoral immune response, a cell-mediated immune response, or an humoral and a cell-mediated immune response.